WO2019038361A1 - Medicaments for the treatment of vasoconstriction related diseases or disorders - Google Patents
Medicaments for the treatment of vasoconstriction related diseases or disorders Download PDFInfo
- Publication number
- WO2019038361A1 WO2019038361A1 PCT/EP2018/072735 EP2018072735W WO2019038361A1 WO 2019038361 A1 WO2019038361 A1 WO 2019038361A1 EP 2018072735 W EP2018072735 W EP 2018072735W WO 2019038361 A1 WO2019038361 A1 WO 2019038361A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- tetramethylchroman
- carboxamide
- sul
- methanone
- Prior art date
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 36
- 230000025033 vasoconstriction Effects 0.000 title claims abstract description 30
- 206010047139 Vasoconstriction Diseases 0.000 title claims abstract description 26
- 238000011282 treatment Methods 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 208000035475 disorder Diseases 0.000 title claims description 24
- 201000010099 disease Diseases 0.000 title claims description 10
- GZCJJOLJSBCUNR-UHFFFAOYSA-N chroman-6-ol Chemical class O1CCCC2=CC(O)=CC=C21 GZCJJOLJSBCUNR-UHFFFAOYSA-N 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- UBQNZKMELMBKHG-UHFFFAOYSA-N (6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)-piperazin-1-ylmethanone Chemical group C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)N1CCNCC1 UBQNZKMELMBKHG-UHFFFAOYSA-N 0.000 claims abstract description 8
- MCJPTWSIETYCSU-UHFFFAOYSA-N (6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)-morpholin-4-ylmethanone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)N1CCOCC1 MCJPTWSIETYCSU-UHFFFAOYSA-N 0.000 claims abstract description 7
- GVRPEPYMMPCDQB-UHFFFAOYSA-N methyl 4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carbonyl)amino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1NC(=O)C1(C)OC2=C(C)C(C)=C(O)C(C)=C2CC1 GVRPEPYMMPCDQB-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000011321 prophylaxis Methods 0.000 claims abstract description 7
- YHDLWWYVEKBXTD-UHFFFAOYSA-N n-benzyl-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carboxamide Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)NCC1=CC=CC=C1 YHDLWWYVEKBXTD-UHFFFAOYSA-N 0.000 claims abstract description 6
- CKXKDKUTMXBCOW-UHFFFAOYSA-N 6-hydroxy-2,5,7,8-tetramethyl-n-phenyl-3,4-dihydrochromene-2-carboxamide Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)NC1=CC=CC=C1 CKXKDKUTMXBCOW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000000069 prophylactic effect Effects 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 34
- 108060003345 Adrenergic Receptor Proteins 0.000 claims description 25
- 102000017910 Adrenergic receptor Human genes 0.000 claims description 25
- -1 piperazin-l-yl Chemical group 0.000 claims description 14
- 230000001404 mediated effect Effects 0.000 claims description 11
- 239000002552 dosage form Substances 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- WRTIMWQNBHGKJM-FUKCDUGKSA-N 2-[[(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,5,7,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)CN1CCC[C@H]1CO WRTIMWQNBHGKJM-FUKCDUGKSA-N 0.000 claims description 4
- 208000003782 Raynaud disease Diseases 0.000 claims description 4
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 4
- 208000007232 portal hypertension Diseases 0.000 claims description 4
- ACWPXQCNGOGEPI-LCQOSCCDSA-N 2-[[[(1S)-2-hydroxy-1-phenylethyl]amino]methyl]-2,5,7,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound OC[C@H](C1=CC=CC=C1)NCC1(OC2=C(C(=C(C(=C2CC1)C)O)C)C)C ACWPXQCNGOGEPI-LCQOSCCDSA-N 0.000 claims description 3
- RVGJGTWZOLYPKT-ZZWBGTBQSA-N 6-hydroxy-N-[(1S)-2-hydroxy-1-phenylethyl]-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carboxamide Chemical compound OC=1C(=C2CCC(OC2=C(C1C)C)(C(=O)N[C@H](CO)C1=CC=CC=C1)C)C RVGJGTWZOLYPKT-ZZWBGTBQSA-N 0.000 claims description 3
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 3
- 208000006029 Cardiomegaly Diseases 0.000 claims description 3
- 206010011703 Cyanosis Diseases 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- 206010024648 Livedo reticularis Diseases 0.000 claims description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 3
- 206010043540 Thromboangiitis obliterans Diseases 0.000 claims description 3
- UBQNZKMELMBKHG-GOSISDBHSA-N [(2R)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl]-piperazin-1-ylmethanone Chemical group Cc1c(C)c2O[C@](C)(CCc2c(C)c1O)C(=O)N1CCNCC1 UBQNZKMELMBKHG-GOSISDBHSA-N 0.000 claims description 3
- BQGMIVFITHIERB-KTQQKIMGSA-N [(2s)-2-(hydroxymethyl)pyrrolidin-1-yl]-(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)methanone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)N1CCC[C@H]1CO BQGMIVFITHIERB-KTQQKIMGSA-N 0.000 claims description 3
- JBBRRAJZYGAEQN-UHFFFAOYSA-N [6-hydroxy-2,8-dimethyl-5,7-di(propan-2-yl)-3,4-dihydrochromen-2-yl]-piperazin-1-ylmethanone Chemical compound C1CC=2C(C(C)C)=C(O)C(C(C)C)=C(C)C=2OC1(C)C(=O)N1CCNCC1 JBBRRAJZYGAEQN-UHFFFAOYSA-N 0.000 claims description 3
- 208000002296 eclampsia Diseases 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 208000038003 heart failure with preserved ejection fraction Diseases 0.000 claims description 3
- IXEOWYNUAYRQIK-UHFFFAOYSA-N n-(4-fluorophenyl)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carboxamide Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)NC1=CC=C(F)C=C1 IXEOWYNUAYRQIK-UHFFFAOYSA-N 0.000 claims description 3
- IKQNSCUNASIWRL-PLEWWHCXSA-N n-[(1r)-2-amino-2-oxo-1-phenylethyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carboxamide Chemical compound C1([C@H](C(N)=O)NC(=O)C2(C)OC=3C(C)=C(C(=C(C)C=3CC2)O)C)=CC=CC=C1 IKQNSCUNASIWRL-PLEWWHCXSA-N 0.000 claims description 3
- SPMIORDLEGBRNU-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromene-2-carboxamide Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)NCC1=CC=C(F)C=C1 SPMIORDLEGBRNU-UHFFFAOYSA-N 0.000 claims description 3
- 230000002455 vasospastic effect Effects 0.000 claims description 3
- PPZWFWVXJZIULP-UHFFFAOYSA-N 6-hydroxy-2,5,7,8-tetramethyl-N-(2-nitrophenyl)-3,4-dihydrochromene-2-carboxamide Chemical compound OC=1C(=C2CCC(OC2=C(C=1C)C)(C(=O)NC1=C(C=CC=C1)[N+](=O)[O-])C)C PPZWFWVXJZIULP-UHFFFAOYSA-N 0.000 claims description 2
- LNTUXFQHPCWHRE-UHFFFAOYSA-N 6-hydroxy-2,5,7,8-tetramethyl-n-(3-nitrophenyl)-3,4-dihydrochromene-2-carboxamide Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)C(=O)NC1=CC=CC([N+]([O-])=O)=C1 LNTUXFQHPCWHRE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000006186 oral dosage form Substances 0.000 claims description 2
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 2
- RZEZIIXRJOPPRA-UHFFFAOYSA-N 2-[[(4-fluorophenyl)methylamino]methyl]-2,5,7,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)CNCC1=CC=C(F)C=C1 RZEZIIXRJOPPRA-UHFFFAOYSA-N 0.000 claims 1
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 claims 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 24
- 229960001802 phenylephrine Drugs 0.000 description 24
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000003981 vehicle Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 15
- 229960001289 prazosin Drugs 0.000 description 15
- 230000004044 response Effects 0.000 description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 13
- 239000011575 calcium Substances 0.000 description 13
- 229910052791 calcium Inorganic materials 0.000 description 13
- 102000001301 EGF receptor Human genes 0.000 description 10
- 108060006698 EGF receptor Proteins 0.000 description 10
- 229960001340 histamine Drugs 0.000 description 10
- 230000002792 vascular Effects 0.000 description 9
- 230000000304 vasodilatating effect Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 8
- 230000003993 interaction Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000000872 buffer Substances 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 230000003834 intracellular effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- 210000001367 artery Anatomy 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical class O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 description 4
- WJAJPNHVVFWKKL-UHFFFAOYSA-N Methoxamine Chemical compound COC1=CC=C(OC)C(C(O)C(C)N)=C1 WJAJPNHVVFWKKL-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229960005192 methoxamine Drugs 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 229910001868 water Inorganic materials 0.000 description 4
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 3
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 3
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 210000003038 endothelium Anatomy 0.000 description 3
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000003032 molecular docking Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000004088 simulation Methods 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AADCDMQTJNYOSS-LBPRGKRZSA-N 5-chloro-3-ethyl-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide Chemical compound CCN1CCC[C@H]1CNC(=O)C1=C(O)C(CC)=CC(Cl)=C1OC AADCDMQTJNYOSS-LBPRGKRZSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 102000003938 Thromboxane Receptors Human genes 0.000 description 2
- 108090000300 Thromboxane Receptors Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000000048 adrenergic agonist Substances 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 230000028956 calcium-mediated signaling Effects 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 210000002254 renal artery Anatomy 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003767 thromboxane receptor stimulating agent Substances 0.000 description 2
- 230000003639 vasoconstrictive effect Effects 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OSNSWKAZFASRNG-WNFIKIDCSA-N (2s,3r,4s,5s,6r)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol;hydrate Chemical compound O.OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O OSNSWKAZFASRNG-WNFIKIDCSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229940121913 Alpha adrenoreceptor antagonist Drugs 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 101150097070 Drd3 gene Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 241000239226 Scorpiones Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- MEAHOCBUVFCKNA-UHFFFAOYSA-N [O].C=1C=COC=1 Chemical compound [O].C=1C=COC=1 MEAHOCBUVFCKNA-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 description 1
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000004289 cerebral ventricle Anatomy 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229950007535 eticlopride Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 230000022082 negative regulation of vasoconstriction Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Natural products CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to medicaments for use in the prophylaxis or treatment of vasoconstriction related disorders or conditions.
- Vasoconstriction related disorder comprise a group of disorders, like for example pulmonary hypertension, portal hypertension, vasospastic diseases, Raynaud's disease, acrocyanosis, livedo reticularis, post-traumatic dystrophy, occlusive diseases associated with inflammation and Buerger's disease.
- Vasoconstriction is the process of constriction of blood vessels, which may result in decrease of flow of blood.
- Normal blood flow is necessary for carrying oxygenated blood to all parts of the body and when the normal flow is disrupted it may cause various problems.
- Vasoconstriction can occur due to medical condition or due to psychological disorder. This condition happens when the small muscles of the walls constrict causing narrowing of blood vessels. Actually this process is exactly opposite condition of vaso-dilation in which the blood vessels enlarge or open widely. The contraction of blood vessels can increase the heat of the body and may cause vascular conflict. Following this condition, the skin becomes paler than before since blood supply is drastically reduced. It occurs mostly on large arteries thus obstructing the blood flow but sometimes it can develop on small arterioles causing constriction of blood vessels.
- alpha adrenoreceptor antagonist (which is a vasodilator) can be administered for reducing the constriction of blood vessels and increasing blood flow. Treating the problem with calcium channel blockers would facilitate widening of blood vessels.
- the 5 main categories of drugs used in the initial treatment of hypertensive vascular diseases are (1). diuretics, (2). beta-adrenergic blockers, (3). calcium channel blockers, (4). angiotensin-converting enzyme (ACE) inhibitors, and (5). angiotensin receptor blockers (ARBs).
- ACE angiotensin-converting enzyme
- ARBs angiotensin receptor blockers
- antihypertensive agents is roughly equally effective, producing a good antihypertensive response in 40% to 60% of cases.
- vasoconstriction related disorders in particular ones that have less side effects, or preferably no side effects at all in the dosing range of such compound. It is an object of the present invention to provide compounds for the treatment of vasoconstriction related disorders or conditions.
- chromanol compounds have been described in e.g. WO2014/098586, WO2015/193365 and WO2016/188766. These compounds show a wide variety of protective effects on cells and organs.
- the compounds described in detail are developed by Sulfateq, and have abbreviations, referring to SUL-XXX (XXX being a 2 or 3 digit number). Many of these compounds are racemic mixtures, although some enantiomers have been tested as well.
- the present invention relates to the (2R) enantiomeric form of a 6-chromanol derivative wherein the 6-chromanol derivative is chosen from the group consisting of (6-hydroxy- 2,5,7, 8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone (SUL- 121); (6-hydroxy-2,5,7,8- tetramethylchroman-2-yl)(morpholino)methanone (SUL-95); N-(benzyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide (SUL-96), N-(4-fluorobenzyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide (SUL-97); 6-hydroxy-N-((S)-2-hydroxy-l-phenylethyl)- 2,5,7, 8-tetramethylchroman-2-carboxamide (SUL-98); N-(phenyl)-6-hydroxy-2,5,
- the chromanol compound is chosen from the group consisting of the 2R enantiomer of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l- yl)methanone; N-(benzyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide; - N-(phenyl)-6- hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide; methyl 4-(6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamido)benzoate; and pharmaceutically acceptable salts thereof.
- the chromanol compound is chosen from the group consisting of the 2R enantiomer of (6-hydroxy-2,5,7,8-tetramethylchroman-2- yl)(morpholino)methanone, and (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l- yl)methanone.
- the present invention relates to the (R) enantiomeric form of a 6-chromanol derivative, wherein said 6-chromanol derivative is (R)(6- hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone and pharmaceutically acceptable salts thereof.
- the present invention relates to the (R) enantiomeric form of a 6-chromanol derivative as described, wherein the vasoconstriction related disorder is selected from the group consisting of pulmonary hypertension, portal hypertension, vasospastic diseases, Raynaud's disease, acrocyanosis, livedo reticularis, posttraumatic dystrophy, occlusive diseases associated with inflammation, (pre)eclampsia, and Buerger's disease.
- Pulmonary hypertension in particular relates to pulmonary arterial hypertension, for which the present invention is preferred.
- Another disorder that can be treated with the described compounds is cardiac hypertrophy and fibrosis.
- the vasoconstriction disorder particularly relates to al adrenoceptor mediated disorders, such as pulmonary arterial hypertension and cardiac hypertrophy and fibrosis.
- HFpEF preserved ejection fraction
- the vasoconstrictive disorder has a co-indication of inflammation.
- the chromanol compounds are effective as anti-inflammatory agents, the use of said chromanol compounds is very effective in the prophylaxis or treatment of vasoconstrictive and inflammation related disorders, such as pulmonary hypertension, portal hypertension and
- SUL-121 is a 1: 1 racemic mixture of two enantiomers (S enantiomer named SUL-
- SUL-150 R enantiomer named SUL-150.
- PE phenylephrine
- the present invention relates to the (R) enantiomeric form of a 6-chromanol derivative, wherein said prophylaxis or treatment of vasoconstriction related disorders or conditions is mediated by inhibition of the al adrenoceptor, ai adrenoceptors are coupled with the G-protein (GPRC), specifically G q and Gn subtypes.
- GPRC G-protein
- Their activation leads to a downstream activation of phospholipase pathways, increase of (Ca 2+ )i and a subsequent constriction of the vascular smooth muscle.
- EGFR Epidermal Growth Factor Receptor
- SUL-150 inhibits vasoconstriction is via direct interaction with the ai adrenoceptor as a receptor antagonist.
- SUL-151 did not affect calcium transients in any of the investigated al adrenoceptor subtypes.
- Results indicate that SUL- 150 is capable of counteracting vascular constriction and intracellular calcium responses specifically via its action on ai adrenoceptors.
- Radiolabeled prazosin displacement suggests that SUL-150 competitively binds to the antagonist binding site.
- Prazosin is an ⁇ -blocker which acts as an inverse agonist at alpha- 1 adrenergic receptors.
- SUL-150 conveys a range of additional beneficial effects.
- Combined anti-oxidant, anti-inflammatory and vasodilatory properties of SUL-150 may be applicable in the treatment of diseases related to vasoconstriction, such as Raynaud's disease.
- the present invention relates to (R)(6-hydroxy- 2,5,7, 8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone, and to the use of said compound and pharmaceutically acceptable salts thereof as a medicament.
- the present invention relates to the 2R-6- chromanol derivative, wherein the prophylaxis or treatment of vasoconstriction related disorders or conditions is mediated by inhibition of the al adrenoceptor.
- the compounds are preferably used in effective amounts, to achieve a vasodilatory effect. Effects are observed with amounts of 1 ⁇ , but preferably higher amounts are used.
- Preferred amounts are concentrations in vivo or in vitro of about 10 ⁇ or higher, more preferably about 20 ⁇ or higher. Generally, a concentration in human of about 200 ⁇ or lower should be sufficient and safe.
- dosage forms of about 20 mg or more, preferably 50 mg or more, preferably 100 mg or more are suitable.
- solid, oral dosage forms contain as a maximum about 500 mg compound, preferably about 450 mg or less, to allow for excipients. With i.v. other liquid forms of administration, larger amounts can be administered.
- Examples of dosages which can be used are an effective amount of the compounds of the invention of a dosage of 0.2 mg kg or higher, such as preferably within the range of about 1 mg /kg to about 100 mg/kg, or within about 2 mg /kg to about 40 mg/kg body weight, or within about 3 mg/kg to about 30 mg/kg body weight, or within about 4 mg /kg to about 15mg/kg body weight.
- Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.
- the compounds described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically or physiologically acceptable excipients carriers, and vehicles.
- suitable pharmaceutically or physiologically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-P-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, and the like, as well as combinations of any two or more thereof.
- processing agents and drug delivery modifiers and enhancers such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-P-cyclodextrin
- a pharmaceutical composition can comprise a unit dose formulation, where the unit dose is a dose sufficient to have an vasodilatory effect, preferably a vasodilatory therapeutic effect.
- the unit dose may be a dose administered periodically in a course of treatment or suppression of a vasodilatory disorder.
- compositions containing the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion.
- Liquid carriers are typically used in preparing solutions, suspensions, and emulsions.
- Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s),
- the liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like.
- suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols.
- Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like.
- the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like.
- Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
- Time-release or controlled release delivery systems may be used, such as a diffusion controlled matrix system or an erodible system, as described for example in: Lee,
- the matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e.g. , by proteases.
- the delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example in the form of a hydrogel.
- Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), poly amides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes ).
- the compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation (e. g. as mists or sprays), rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically or physiologically acceptable carriers, adjuvants, and vehicles as desired.
- suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e. g. via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue.
- Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
- the compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration.
- Oral administration is a preferred route of administration, and formulations suitable for oral administration are preferred formulations.
- the compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms.
- the compounds can also be administered in liposome formulations.
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol.
- a nontoxic parenterally acceptable diluent or solvent for example, as a solution in propylene glycol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
- a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
- Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
- Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
- the invention also provides articles of manufacture and kits containing materials useful for treating, preventing, or suppressing symptoms associated with vasodilatory related conditions or disorders.
- the article of manufacture comprises a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic.
- the container holds a composition having an active agent which is effective for treating, preventing, or suppressing symptoms associated with a vasodilatory disorder or with a condition associated with vasodilatory dysfunction.
- the active agent in the composition is one or more of the compounds of the invention.
- the label on the container preferably indicates that the composition is used for treating, preventing, or suppressing symptoms associated with a vasodilatory related disorder or condition, and may also indicate directions for either in vivo or in vitro use, such as those described above.
- kits comprising any one or more of the compounds of the invention.
- the kit of the invention comprises the container described above.
- the kit of the invention comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease undergoing therapy or condition to be treated.
- the unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other targeted region of the body. The effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician or skilled person.
- Figure 1 Shows the constriction responses to phenylephrine (PE) in the presence of different doses of SUL-150 (B) and SUL-151 (C). Methoxamine-induced vasoconstriction was measured with intact endothelium (D) and endothelium-denuded rings (E) in the presence of vehicle (0.1% DMSO) and two dosages (30 ⁇ and ⁇ ) of
- Figure 2 Shows constriction responses to histamine (A) and the thromboxane agonist
- Figure 3 Shows constriction responses to phenylephrine in the presence of vehicle and three concentrations of the EGFR inhibitor AG1478 (A) and 20 ⁇ AG1478 with 50 ⁇ SUL-150 (B).
- Figure 4 Shows intracellular calcium measurements in transgenic CHO cells overexpressing
- Figure 5 Shows displacement of tritium-labelled prazosin by SUL-150 and SUL-151 in di A
- FIG. 6 Shows the structural formula of the SUL-121 ((6-hydroxy-2,5,7,8- tetramethylchroman-2-yl)-(piperaziniyl)-methanone) compound.
- SUL-121 is a racemic 1: 1 mixture of (R)-enantiomer SUL-150 and (S)-enantiomer SUL-151.
- the * indicates the chiral centre of SUL-121 in the structural formula, which is at the 2 position in the chromanol group. Therefore, generally, the group of enantiomers is named the "2-R enantiomer of.
- Porcine kidneys were obtained from a local slaughterhouse (Kroon Vlees, Gotenburgweg 30, 9723 TM Groningen, The Netherlands) and transported on ice in normal physiological Krebs buffer containing 120 mM NaCl, 6 mM KCl, 2.5 mM CaCl 2 x 2H 2 0, 1.2 mM MgCl 2 x 6H 2 0, 1.2 mM NaH 2 P0 4 x H 2 0, 25 mM NaHC0 3 and 11.4 mM D-(+)-Glucose monohydrate (all ingredients were purchased from Merck) in ultrapure water.
- the renal artery tree was dissected from the kidney, cleaned of surrounding connective tissue and cut into equally-sized ring segments (2 mm in length). In some rings, endothelium denudation was performed by gentle rubbing of the intimal surface with a paper clip. Rings were mounted in organ baths as described previously (Buikema et al., 2000). Arterial rings were washed thoroughly by replacing Krebs buffer and allowed to equilibrate for a period of 60 min under 1.4g of resting tension before they were assessed for viability by inducing 2 subsequent constrictions with KCl (60mM). Rings that failed to produce a threshold increase in diameter of ⁇ were excluded. After washout and stabilization, rings were treated for 30 minutes by incubation with vehicle (0.1% DMSO), SUL-121, SUL-150 or SUL-151, followed by subsequent incubation with cumulative doses of phenylephrine.
- vehicle (0.1% DMSO
- SUL-121, SUL-150 or SUL-151 followed
- Cell culture CHO-K1 cells were stably transfected with a plasmid containing human al-AR subtypes A, B and D in separate cell lines in DMEM-F12 medium with 10% FBS, 1% penicillin- streptomycin and 200 g/mL Geneticin (G418, Invitrogen, Carlsbad, CA).
- HeLa cells endogenously expressing histamine and TP receptors were grown in DMEM-F12 medium enriched with 10% FBS and 1% penicillin-streptomycin. Cells were kept in a tissue culture incubator at 37°C in 5% 0 2 / 95% C0 2 atmosphere and grown in 75cm 2 non-treated cell culture flasks. Plating was performed 24 hours before measurement on black transparent- bottom 96-well plates at 20,000 cells per well density.
- Example 3 Example 3:
- CHO cells were treated with either vehicle (0.1% DMSO) or SUL-121 enantiomers for 30 min at 37°C and stimulated with a 3-fold dilution series of PE (20 ⁇ - ⁇ ).
- [Ca 2+ ]i was measured using the fluorescent FLIPR Calcium 6 assay kit (Molecular Devices) in immortalized CHO cells stably expressing the ⁇ adrenoceptor.
- the "Vehicle” used in all experiments is 0.1% DMSO solution.
- Vascular constriction responses are expressed as percentage of final response to KC1. Data are expressed as mean + SEM. *p ⁇ 0.05.
- the primary sequence of di A adrenoceptor was obtained from UniProt database (The UniProt Consortium, 2017) using reference code P35348 and uploaded to SWISS-MODEL in order to build a homology model, resulting in 373 templates. Subsequently, template ligand codes were used to query the PDB database to obtain structural data in SMILES format, which were processed by Chemmine to detect similarities with SUL-150.
- the SWISS-MODEL template that contained a ligand with the highest similarity score (a D3 dopamine receptor in complex with, Eticlopride, ETQ) was used to align the di A -AR sequence onto a modelled backbone.
- the resulting homology model was validated by Ramachandran plot and prepared with Protein Preparation Wizard by the addition of hydrogens, bond order assignment, generation of partial charges to heteroatoms and disulfide bonds. Final refinement was performed by hydrogen bond assignment at pH 7.4 and restrained minimization at 0.3 RMSD.
- Prazosin, SUL-150 and SUL-151 structural files were converted from SMILES to 3D structures using LigPrep. Protonation states were generated with Epik at pH 7.4 and small molecule energy parameters were computed using OPLS3 forcefield.
- Table 1 LogECso values of phenylephrine-induced constriction responses in the presence
- Table 2 LogECso values of histamine and U46619-induced constriction responses in the presence of SUL-150.
- SUL-150 are upstream of calcium. We therefore explored whether SUL-150 could directly interact with the ai adrenoceptor as a receptor antagonist. For this, a displacement binding assay was performed on the (Xi A adrenoceptor transgenic CHO cells using radiolabeled prazosin, an established (Xi A adrenoceptor antagonist. SUL- 150 was more potent in displacing the radioligand compared to SUL-151, which displaced [7-Methoxy-3H]-prazosin only at concentrations higher than 10 ⁇ (Figure 5).
- Prazosin coexists in two protonation forms at pH 7.4.
- the Nl assumes a positive charge, subsequently forming a salt bridge with the negatively charged side chain of ASP106, ultimately causing this form to assume an inverted orientation relative to its non- protonated form.
- the quinazoline scaffold of non-protonated prazosin was docked close to TM5 to form a confocal hydrogen bond between the 6,7-methoxy groups and SER188, a hydrogen bond between furan oxygen and SER83, and between prazosin carboxamide and GLN177 side chain; van der Waals interactions with side chains of PHE86, VAL107, ILE178, PHE289, MET292, and PHE312; ⁇ - ⁇ interactions with PHE288 and PHE312; and a ⁇ -hydrogen bond interaction with the side chain carboxy group and backbone peptide carboxamide of ASP106.
- the proposed binding mode of non-protonated prazosin indicated interactions which were in accord with those described in the literature.
- SUL-150 and SUL-151 demonstrated alignment of the chromane scaffold with prazosin quinazoline, 6-hydroxy groups (SUL) and 6-metoxy (prazosin) as well as over their common piperazine moiety.
- Residues which were involved in forming contacts with all three compounds were VAL107, ILE178, SER188, PHE288, PHE289.
- Glide scores computed using the Schrodinger Small-Drug Discovery Suite were - 10.8 kcalxmol "1 , -10.2 kcalxmol 1 and -9.4 kcalxmol 1 for prazosin, SUL-150 and SUL-151 respectively.
- Prazosin and SUL-150 formed contacts with PHE312 and ASP106 confirmed in prazosin binding by mutagenesis, whereas SUL-151 did not show interactions with these residues. Additionally, the chirality of SUL-150 enables the orientation of its carboxamide towards ASN179, effectively forming a hydrogen bond. Additional hydrogen bond was formed between its protonated N- terminal and TYR316.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medicaments for use in the prophylaxis or treatment of vasoconstriction related disorders or conditions. Specifically, the present invention relates to (2R) enantiomeric form of a 6-chromanol derivative for use in the prophylactic or treatment of vasoconstriction related disorders or conditions. A preferred 6-chromanol derivative is (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone; N-(benzyl)-6-hydroxy- 2,5,7, 8-tetramethylchroman-2-carboxamide; N-(phenyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxamide; methyl 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)benzoate; (6- hydroxy-2,5,7,8-tetramethylchroman-2-yl)(morpholino)methanone, and pharmaceutically acceptable salts thereof.
Description
MEDICAMENTS FOR THE TREATMENT OF VASOCONSTRICTION RELATED
DISEASES OR DISORDERS
DESCRIPTION
The present invention relates to medicaments for use in the prophylaxis or treatment of vasoconstriction related disorders or conditions.
Vasoconstriction related disorder comprise a group of disorders, like for example pulmonary hypertension, portal hypertension, vasospastic diseases, Raynaud's disease, acrocyanosis, livedo reticularis, post-traumatic dystrophy, occlusive diseases associated with inflammation and Buerger's disease.
Vasoconstriction is the process of constriction of blood vessels, which may result in decrease of flow of blood. Normal blood flow is necessary for carrying oxygenated blood to all parts of the body and when the normal flow is disrupted it may cause various problems.
Vasoconstriction can occur due to medical condition or due to psychological disorder. This condition happens when the small muscles of the walls constrict causing narrowing of blood vessels. Actually this process is exactly opposite condition of vaso-dilation in which the blood vessels enlarge or open widely. The contraction of blood vessels can increase the heat of the body and may cause vascular conflict. Following this condition, the skin becomes paler than before since blood supply is drastically reduced. It occurs mostly on large arteries thus obstructing the blood flow but sometimes it can develop on small arterioles causing constriction of blood vessels.
An alpha adrenoreceptor antagonist (which is a vasodilator) can be administered for reducing the constriction of blood vessels and increasing blood flow. Treating the problem with calcium channel blockers would facilitate widening of blood vessels.
Control of hypertension in the vascular patient is clearly a priority. However, these patients often will have significant co-morbidities that may influence the choice of medication. The 5 main categories of drugs used in the initial treatment of hypertensive vascular diseases are (1). diuretics, (2). beta-adrenergic blockers, (3). calcium channel blockers, (4). angiotensin-converting enzyme (ACE) inhibitors, and (5). angiotensin receptor blockers (ARBs). Each of the
antihypertensive agents is roughly equally effective, producing a good antihypertensive response in 40% to 60% of cases. Some antihypertensives, especially ACE and ARBs, also may have beneficial effects on the vascular and metabolic systems separate from their blood pressure lowering effects, which suggests they may be beneficial even if blood pressure is well maintained with other agents.
However, there remains a need for new compounds for treatment of vasoconstriction related disorders, in particular ones that have less side effects, or preferably no side effects at all in the dosing range of such compound.
It is an object of the present invention to provide compounds for the treatment of vasoconstriction related disorders or conditions.
The above object is met by the present invention by the (2R) enantiomeric form of certain 6-chromanol derivatives for use in the treatment of vasoconstriction related disorders or conditions.
Certain chromanol compounds have been described in e.g. WO2014/098586, WO2015/193365 and WO2016/188766. These compounds show a wide variety of protective effects on cells and organs. The compounds described in detail are developed by Sulfateq, and have abbreviations, referring to SUL-XXX (XXX being a 2 or 3 digit number). Many of these compounds are racemic mixtures, although some enantiomers have been tested as well.
Unexpectedly, upon further research, a number of the SUL compounds showed reversal effects of vascular constriction, which effect is useful in the treatment of vasoconstriction related disorders.
Thus, the present invention relates to the (2R) enantiomeric form of a 6-chromanol derivative wherein the 6-chromanol derivative is chosen from the group consisting of (6-hydroxy- 2,5,7, 8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone (SUL- 121); (6-hydroxy-2,5,7,8- tetramethylchroman-2-yl)(morpholino)methanone (SUL-95); N-(benzyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide (SUL-96), N-(4-fluorobenzyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide (SUL-97); 6-hydroxy-N-((S)-2-hydroxy-l-phenylethyl)- 2,5,7, 8-tetramethylchroman-2-carboxamide (SUL-98); N-(phenyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide (SUL- 103); 6-hydroxy-2,5,7,8-tetramethyl-N-(2- nitrophenyl)chroman-2-carboxamide (SUL- 104); 6-hydroxy-2,5,7,8-tetramethyl-N-(3- nitrophenyl)chroman-2-carboxamide (SUL- 105); N-(4-fluorophenyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide (SUL-106); methyl 4-(6-hydroxy-2,5,7,8-tetramethylchroman- 2-carboxamido)benzoate (SUL-107); N-( (R)-2-amino-2-oxo-l-phenylethyl)-6-hydroxy-2,5, 7,8- tetramethylchroman-2-carboxamide (SUL-111); (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)((S)- 2-(hydroxymethyl )pyrrolidin-l-yl )methanone (SUL-112); 2-(((4-fluorobenzyl)amino)mefhyl)- 2,5,7, 8-tetramethylchroman-6-ol (SUL-116); 2-(((S)-2-(hydroxymethyl)pyrrolidin-l-yl)methyl)- 2,5,7, 8-tetramethylchroman-6-ol (SUL- 128); 2-((((S)-2-hydroxy-l-phenylethyl)amino)methyl)- 2,5,7,8-tetramethvlchroman-6-ol (SUL-129); 2-(((S)-2-(hydroxymethyl)pyrrolidin-l-yl)methyl)- 2,5,7, 8-tetramethvlchroman-6-ol (SUL- 134); 2-(((R-2-(hydroxymethyl)pyrrolidin-l-yl)methyl)- 2,5,7, 8-tetramethylchroman-6-ol (SUL135); ( 6-hydroxy-5, 7-diisopropyl-2,8-dimethylchroman-2- yl)(piperazin-l-yl)methanone (SUL-137); l-( 6-hydroxy-2,5, 7 ,8-tetramethylchroman-2-carbonyl )-pyrrolidine-S-2-carboxvlic acid (SUL-143) and pharmaceutically acceptable salts thereof.
In a preferred embodiment, the chromanol compound is chosen from the group consisting of the 2R enantiomer of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l-
yl)methanone; N-(benzyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide; - N-(phenyl)-6- hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide; methyl 4-(6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamido)benzoate; and pharmaceutically acceptable salts thereof.
In another particularly preferred embodiment, the chromanol compound is chosen from the group consisting of the 2R enantiomer of (6-hydroxy-2,5,7,8-tetramethylchroman-2- yl)(morpholino)methanone, and (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l- yl)methanone.
According to a most preferred embodiment, the present invention relates to the (R) enantiomeric form of a 6-chromanol derivative, wherein said 6-chromanol derivative is (R)(6- hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone and pharmaceutically acceptable salts thereof.
According to yet another preferred embodiment, the present invention relates to the (R) enantiomeric form of a 6-chromanol derivative as described, wherein the vasoconstriction related disorder is selected from the group consisting of pulmonary hypertension, portal hypertension, vasospastic diseases, Raynaud's disease, acrocyanosis, livedo reticularis, posttraumatic dystrophy, occlusive diseases associated with inflammation, (pre)eclampsia, and Buerger's disease. Pulmonary hypertension in particular relates to pulmonary arterial hypertension, for which the present invention is preferred. Another disorder that can be treated with the described compounds is cardiac hypertrophy and fibrosis.
The vasoconstriction disorder particularly relates to al adrenoceptor mediated disorders, such as pulmonary arterial hypertension and cardiac hypertrophy and fibrosis.
Another indication which is preferably treated with the compounds of the present invention is heart failure with preserved ejection fraction (HFpEF), in which hypertension generally is co-indicated.
In a preferred embodiment, the vasoconstrictive disorder has a co-indication of inflammation. As the chromanol compounds are effective as anti-inflammatory agents, the use of said chromanol compounds is very effective in the prophylaxis or treatment of vasoconstrictive and inflammation related disorders, such as pulmonary hypertension, portal hypertension and
(pre)eclampsia.
SUL-121 is a 1: 1 racemic mixture of two enantiomers (S enantiomer named SUL-
151, R enantiomer named SUL-150). The effects of SUL-150 and SUL-151 on phenylephrine (PE) -induced vascular constrictions were investigated. The results showed that whereas SUL-150 exerted a dose-dependent increase of EC50, whereas no significant effects after treatment with SUL-151 were observed. The SUL-150 was able to inhibit or counteract the induced vascular constrictions.
According to a preferred embodiment, the present invention relates to the (R) enantiomeric form of a 6-chromanol derivative, wherein said prophylaxis or treatment of vasoconstriction related disorders or conditions is mediated by inhibition of the al adrenoceptor, ai adrenoceptors are coupled with the G-protein (GPRC), specifically Gq and Gn subtypes. Their activation leads to a downstream activation of phospholipase pathways, increase of (Ca2+)i and a subsequent constriction of the vascular smooth muscle. Additionally, we have demonstrated the ability of ai adrenoceptors to trans-activate the Epidermal Growth Factor Receptor (EGFR) which contributes to downstream phosphorylation of extracellular signal-regulated kinases 1 and 2. The inhibition of EGFR attenuated constriction responses to PE in isolated rat aortas. Therefore, we investigate the effects of SUL-150 on the mechanism of EGFR transactivation by al
adrenoceptors.
It was found that the mechanism through which SUL-150 inhibits vasoconstriction is via direct interaction with the ai adrenoceptor as a receptor antagonist. SUL-151 did not affect calcium transients in any of the investigated al adrenoceptor subtypes. Results indicate that SUL- 150 is capable of counteracting vascular constriction and intracellular calcium responses specifically via its action on ai adrenoceptors. Radiolabeled prazosin displacement suggests that SUL-150 competitively binds to the antagonist binding site. Prazosin is an αι-blocker which acts as an inverse agonist at alpha- 1 adrenergic receptors. Compared with prazosin, SUL-150 conveys a range of additional beneficial effects. Combined anti-oxidant, anti-inflammatory and vasodilatory properties of SUL-150 may be applicable in the treatment of diseases related to vasoconstriction, such as Raynaud's disease.
The present invention, according to a further aspect, relates to (R)(6-hydroxy- 2,5,7, 8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone, and to the use of said compound and pharmaceutically acceptable salts thereof as a medicament.
According to preferred embodiment, the present invention relates to the 2R-6- chromanol derivative, wherein the prophylaxis or treatment of vasoconstriction related disorders or conditions is mediated by inhibition of the al adrenoceptor.
The compounds are preferably used in effective amounts, to achieve a vasodilatory effect. Effects are observed with amounts of 1 μΜ, but preferably higher amounts are used.
Preferred amounts are concentrations in vivo or in vitro of about 10 μΜ or higher, more preferably about 20 μΜ or higher. Generally, a concentration in human of about 200 μΜ or lower should be sufficient and safe.
For human use, this would mean - assuming a 30 L distribution volume, 100% availability and a concentration of about 1 μΜ - a dosage of about 10 mg or more. Preferred amounts would result in a concentration of about 10 μΜ - for which a dosage of about 100 mg or more would be suitable. Hence, preferably, dosage forms of about 20 mg or more, preferably 50
mg or more, preferably 100 mg or more are suitable. Generally, solid, oral dosage forms contain as a maximum about 500 mg compound, preferably about 450 mg or less, to allow for excipients. With i.v. other liquid forms of administration, larger amounts can be administered.
Examples of dosages which can be used are an effective amount of the compounds of the invention of a dosage of 0.2 mg kg or higher, such as preferably within the range of about 1 mg /kg to about 100 mg/kg, or within about 2 mg /kg to about 40 mg/kg body weight, or within about 3 mg/kg to about 30 mg/kg body weight, or within about 4 mg /kg to about 15mg/kg body weight. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosage of two, three or four times daily.
The compounds described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically or physiologically acceptable excipients carriers, and vehicles. Suitable pharmaceutically or physiologically acceptable excipients, carriers and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-P-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, and the like, as well as combinations of any two or more thereof. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences, " Mack Pub. Co. , New Jersey (1991), and "Remington: The Science and Practice of Pharmacy, " Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003) and 21 " edition (2005) .
A pharmaceutical composition can comprise a unit dose formulation, where the unit dose is a dose sufficient to have an vasodilatory effect, preferably a vasodilatory therapeutic effect. The unit dose may be a dose administered periodically in a course of treatment or suppression of a vasodilatory disorder.
Pharmaceutical compositions containing the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions, suspensions, and emulsions. Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s),
pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl
myristate, and the like. Compositions of the present invention may also be in the form of microparticles, microcapsules, liposomal encapsulates, and the like, as well as combinations of any two or more thereof.
Time-release or controlled release delivery systems may be used, such as a diffusion controlled matrix system or an erodible system, as described for example in: Lee,
"Diffusion-Controlled Matrix Systems", pp. 155-198 and Ron and Langer, "Erodible Systems", pp. 199-224, in "Treatise on Controlled Drug Delivery", A Kydonieus Ed. , Marcel Dekker, Inc. , New York 1992. The matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e.g. , by proteases. The delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), poly amides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes ).
The compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation (e. g. as mists or sprays), rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically or physiologically acceptable carriers, adjuvants, and vehicles as desired. For example, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e. g. via nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly to a specific or affected organ or tissue. For delivery to the central nervous system, spinal and epidural administration, or administration to cerebral ventricles, can be used. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. The compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration.
Oral administration is a preferred route of administration, and formulations suitable for oral administration are preferred formulations.
The compounds described for use herein can be administered in solid form, in liquid form, in aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injectables, creams, solutions, suppositories, enemas, colonic irrigations, emulsions, dispersions, food premixes, and in other suitable forms. The compounds can also be administered in liposome formulations.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable
solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in propylene glycol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
The invention also provides articles of manufacture and kits containing materials useful for treating, preventing, or suppressing symptoms associated with vasodilatory related conditions or disorders. The article of manufacture comprises a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition having an active agent which is effective for treating, preventing, or suppressing symptoms associated with a vasodilatory disorder or with a condition associated with vasodilatory dysfunction. The active agent in the composition is one or more of the compounds of the invention. The label on the container preferably indicates that the composition is used for treating, preventing, or suppressing symptoms associated with a vasodilatory related disorder or condition, and may also indicate directions for either in vivo or in vitro use, such as those described above.
The invention also provides kits comprising any one or more of the compounds of the invention. In some embodiments, the kit of the invention comprises the container described above. In other embodiments, the kit of the invention comprises the container described above and a second container comprising a buffer. It may further include other materials desirable from a
commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods described herein.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host to which the active ingredient is administered and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body area, body mass index (BMI), general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the type, progression, and severity of the particular disease undergoing therapy or condition to be treated. The unit dosage chosen is usually fabricated and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other targeted region of the body. The effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician or skilled person.
The present invention will be further illustrated using the examples below. In the examples, reference is made to figures wherein
Figure 1: Shows the constriction responses to phenylephrine (PE) in the presence of different doses of SUL-150 (B) and SUL-151 (C). Methoxamine-induced vasoconstriction was measured with intact endothelium (D) and endothelium-denuded rings (E) in the presence of vehicle (0.1% DMSO) and two dosages (30μΜ and ΙΟΟμΜ) of
SUL-150. Data is obtained from 2-3 experiments (n=4-6 per group). Constriction in Figures IB and 1C is expressed as percentage of response to final PE addition.
Figure 2: Shows constriction responses to histamine (A) and the thromboxane agonist
U46619 (B) after pre-treatment with vehicle (0.1% DMSO) and two dosages (30μΜ and ΙΟΟμΜ) of SUL-150.
Figure 3: Shows constriction responses to phenylephrine in the presence of vehicle and three concentrations of the EGFR inhibitor AG1478 (A) and 20μΜ AG1478 with 50μΜ SUL-150 (B).
Figure 4: Shows intracellular calcium measurements in transgenic CHO cells overexpressing
(Xi adrenoceptor subtypes A (A), B (B) and D (C) after stimulation with phenylephrine in the presence of vehicle (10% DMSO), 10μΜ, 30μΜ or ΙΟΟμΜ SUL-150. Figure D shows the lack of effect of SUL-151. Figures E and F show intracellular calcium transients mediated by histamine and U46619, respectively, in HeLa cells after treatment with SUL-150.
Figure 5: Shows displacement of tritium-labelled prazosin by SUL-150 and SUL-151 in diA
adrenoceptor transgenic CHO cells.
Figure 6: Shows the structural formula of the SUL-121 ((6-hydroxy-2,5,7,8- tetramethylchroman-2-yl)-(piperaziniyl)-methanone) compound. SUL-121 is a racemic 1: 1 mixture of (R)-enantiomer SUL-150 and (S)-enantiomer SUL-151. The * indicates the chiral centre of SUL-121 in the structural formula, which is at the 2 position in the chromanol group. Therefore, generally, the group of enantiomers is named the "2-R enantiomer of.
Examples Example 1:
Tissue preparation and myography in isolated porcine renal arteries
Porcine kidneys were obtained from a local slaughterhouse (Kroon Vlees, Gotenburgweg 30, 9723 TM Groningen, The Netherlands) and transported on ice in normal physiological Krebs buffer containing 120 mM NaCl, 6 mM KCl, 2.5 mM CaCl2 x 2H20, 1.2 mM MgCl2 x 6H20, 1.2 mM NaH2P04 x H20, 25 mM NaHC03 and 11.4 mM D-(+)-Glucose monohydrate (all ingredients were purchased from Merck) in ultrapure water.
The renal artery tree was dissected from the kidney, cleaned of surrounding connective tissue and cut into equally-sized ring segments (2 mm in length). In some rings, endothelium denudation was performed by gentle rubbing of the intimal surface with a paper clip. Rings were mounted in organ baths as described previously (Buikema et al., 2000). Arterial rings were washed thoroughly by replacing Krebs buffer and allowed to equilibrate for a period of 60 min under 1.4g of resting tension before they were assessed for viability by inducing 2 subsequent constrictions with KCl (60mM). Rings that failed to produce a threshold increase in diameter of ΙΟΟμιη were excluded. After washout and stabilization, rings were treated for 30 minutes by incubation with vehicle (0.1% DMSO), SUL-121, SUL-150 or SUL-151, followed by subsequent incubation with cumulative doses of phenylephrine.
Dose-dependent constriction responses to phenylephrine (10 8M - 104M) were recorded in said isolated porcine intrarenal arteries. Buffer was warmed to 37°C and aerated with 95 % 02 and 5 % C02 before use.
Example 2:
Cell culture
CHO-K1 cells were stably transfected with a plasmid containing human al-AR subtypes A, B and D in separate cell lines in DMEM-F12 medium with 10% FBS, 1% penicillin- streptomycin and 200 g/mL Geneticin (G418, Invitrogen, Carlsbad, CA).
HeLa cells endogenously expressing histamine and TP receptors were grown in DMEM-F12 medium enriched with 10% FBS and 1% penicillin-streptomycin. Cells were kept in a tissue culture incubator at 37°C in 5% 02 / 95% C02 atmosphere and grown in 75cm2 non-treated cell culture flasks. Plating was performed 24 hours before measurement on black transparent- bottom 96-well plates at 20,000 cells per well density. Example 3:
Intracellular calcium assays
On the next day, CHO cells were treated with either vehicle (0.1% DMSO) or SUL-121 enantiomers for 30 min at 37°C and stimulated with a 3-fold dilution series of PE (20μΜ- ΙΟΟρΜ). [Ca2+]i was measured using the fluorescent FLIPR Calcium 6 assay kit (Molecular Devices) in immortalized CHO cells stably expressing the \ adrenoceptor.
Initially, calcium responses induced by non-cumulative concentration series of phenylephrine were investigated using fluorescent measurements in diA adrenoceptor- overexpressing CHO cells treated with SUL-150 and SUL-151 (Figure 4). Fluorescent measurement data was processed and analyzed in SoftMax Pro 7 and expressed as % of baseline AUC with a 3-fold multiplier using an average of first 10 measurement points as baseline.
The "Vehicle" used in all experiments is 0.1% DMSO solution.
Data and statistical analysis
Vascular constriction responses are expressed as percentage of final response to KC1. Data are expressed as mean + SEM. *p < 0.05.
Example 4 Induced fit molecular docking simulation
The binding of SUL-150 to the antagonist binding site on the aiA-AR, induced fit molecular docking simulation was performed, using prazosin as a reference as follows.
The primary sequence of diA adrenoceptor was obtained from UniProt database (The UniProt Consortium, 2017) using reference code P35348 and uploaded to SWISS-MODEL in order to build a homology model, resulting in 373 templates. Subsequently, template ligand codes were used to query the PDB database to obtain structural data in SMILES format, which were
processed by Chemmine to detect similarities with SUL-150. The SWISS-MODEL template that contained a ligand with the highest similarity score (a D3 dopamine receptor in complex with, Eticlopride, ETQ) was used to align the diA-AR sequence onto a modelled backbone. The resulting homology model was validated by Ramachandran plot and prepared with Protein Preparation Wizard by the addition of hydrogens, bond order assignment, generation of partial charges to heteroatoms and disulfide bonds. Final refinement was performed by hydrogen bond assignment at pH 7.4 and restrained minimization at 0.3 RMSD.
Prazosin, SUL-150 and SUL-151 structural files were converted from SMILES to 3D structures using LigPrep. Protonation states were generated with Epik at pH 7.4 and small molecule energy parameters were computed using OPLS3 forcefield.
Flexible molecular docking simulation was performed using Induced Fit, part of the Schrodinger Small-Molecule Drug Discovery suite. A binding centroid was defined between residues involved in antagonist binding confirmed by mutagenesis (PHE312, PHE308 and ASP106) and ligands were docked within 15A, using an extended sampling protocol without constrains. Residues within 5A of resulting ligand poses were refined using Prime to improve ligand conformational sampling. Finally, the Scorpion server was used for the assessment and classification of small molecule-protein interactions and the final results were rendered using PyMOL 2.0. Results
Effects of SUL-150 and SUL-151 on σ.ι adrenoceptor mediated vasoconstriction
To explore the effects of the enantiomers of (6-hydroxy-2,5,7,8- tetramethylchroman-2-yl)(piperazin- l-yl)methanone (SUL-150 and SUL-151) on constriction of isolated porcine intrarenal arteries, cumulative dose response curves to the x adrenoceptor agonist phenylephrine (PE) were constructed in the presence and absence of SUL-150 and SUL-151. The results are presented in Table 1.
Table 1: LogECso values of phenylephrine-induced constriction responses in the presence
SUL-150 and SUL-151.
Phenylephrine
SUL-150 SUL-151
Vehicle -5.77+0.04
10μΜ -5.11+0.09* -5.82+0.05
30μΜ -5.06+0.06* -5.89+0.04*
ΙΟΟμΜ -4.44+0.09* -5.77+0.04
# p < 0.05 vs vehicle, * p < 0.0001 vs vehicle
Whereas SUL-150 exerted a dose-dependent increase of EC50 (Figure 1 A, Table 1), we observed no significant effects after treatment with SUL-151 (Figure IB, Table 1).
Additionally, the effects of SUL-150 were investigated on stimulation with methoxamine, which is an alternative ai adrenoceptor agonist. Similar to PE, dose response curves to methoxamine were shifted rightward by SUL-150 pre-treatment (Figure 1C). Removal of the endothelium did not abrogate the effects of SUL-150 on methoxamine induced constriction (Figure ID).
Effects of SUL-150 on histamine and U46619 induced vasoconstriction
To gain insight into receptor specificity of SUL-150, the effects of SUL-150 on histamine and U46619 (a synthetic thromboxane agonist) induced constrictions were investigated (Figure 2). SUL-150 did not affect constriction responses to histamine (Table 2) and although the shift in EC50 of U46619-induced constrictions in the presence of ΙΟΟμΜ SUL-150 was statistically significant (Table 2), the small effect size led us to exclude an action of SUL-150 on thromboxane receptors.
Table 2: LogECso values of histamine and U46619-induced constriction responses in the presence of SUL-150.
* p < 0.05 versus vehicle
Effects of SUL-150 mediated through EGFR transactivation
Inhibition of EGF receptor (EGFR) transactivation is known to inhibit ai adrenoceptor mediated constrictions (REF). Therefore, we investigated the role of EGFR transactivation in SUL-150 mediated inhibition of vasoconstriction. For this, porcine intrarenal arteries were pre-treated with the EGFR blocker AG1478 (Figure 3). First, an initial measurement was performed to determine the dose of AG1478 which would cause maximal inhibition of vascular constriction induced by PE (Figure 3A). Subsequently, isolated arteries were treated with AG1478 (20μΜ) and SUL- 150 (50μΜ) and studied for PE-induced vasoconstriction. Despite maximal inhibition of EGFR transactivation by AG1478, SUL-150 still demonstrated an additional inhibitory effect on PE-mediated constriction (Figure 3B).
Effects of SUL-150 on PE-induced intracellular calcium signalling
To further investigate the mechanisms through which SUL-150 inhibits ai adrenoceptor mediated contractions, PE-induced calcium transients were studied in CHO cells stably overexpressing the human ai adrenoceptor subtypes A, B and D. SUL-150 shifted dose response curves rightwards for all three ai adrenoceptor subtypes (Figure 4A, B and C, Table 3). SUL-151 did not affect calcium transients in any of the investigated ai adrenoceptor subtypes (only shown for the ai adrenoceptor A subtype in Figure 4D).
Table 3: LogECso values of phenylephrine-induced calcium influx after treatment with SUL-
150.
* p < 0.0001 versus vehicle
Effects of SUL-150 on histamine- and U46619-induced intracellular calcium signalling
To confirm specificity of SUL-150 for the ai adrenoceptor additionally histamine and U46619 induced calcium transients were studied in HeLa cells endogenously expressing human histamine Hi receptor. SUL-150 did not significantly affect histamine and U46619 induced calcium transients (Figures 4E, 4F and Table 2).
Radioligand binding assay in O.IA adrenoceptor overexpressing CHO cells
SUL-150 affected PE-induced calcium transients, indicating that the effects of
SUL-150 are upstream of calcium. We therefore explored whether SUL-150 could directly interact with the ai adrenoceptor as a receptor antagonist. For this, a displacement binding assay was performed on the (XiA adrenoceptor transgenic CHO cells using radiolabeled prazosin, an established (XiA adrenoceptor antagonist. SUL- 150 was more potent in displacing the radioligand compared to SUL-151, which displaced [7-Methoxy-3H]-prazosin only at concentrations higher than 10μΜ (Figure 5).
Induced fit molecular modelling
Prazosin coexists in two protonation forms at pH 7.4. In the protonated form, the Nl assumes a positive charge, subsequently forming a salt bridge with the negatively charged side chain of ASP106, ultimately causing this form to assume an inverted orientation relative to its non- protonated form. The quinazoline scaffold of non-protonated prazosin was docked close to TM5 to form a confocal hydrogen bond between the 6,7-methoxy groups and SER188, a hydrogen bond
between furan oxygen and SER83, and between prazosin carboxamide and GLN177 side chain; van der Waals interactions with side chains of PHE86, VAL107, ILE178, PHE289, MET292, and PHE312; π-π interactions with PHE288 and PHE312; and a π-hydrogen bond interaction with the side chain carboxy group and backbone peptide carboxamide of ASP106. The proposed binding mode of non-protonated prazosin indicated interactions which were in accord with those described in the literature.
An induced fit of SUL-150 and SUL-151 demonstrated alignment of the chromane scaffold with prazosin quinazoline, 6-hydroxy groups (SUL) and 6-metoxy (prazosin) as well as over their common piperazine moiety. Residues which were involved in forming contacts with all three compounds were VAL107, ILE178, SER188, PHE288, PHE289.
Glide scores computed using the Schrodinger Small-Drug Discovery Suite were - 10.8 kcalxmol"1, -10.2 kcalxmol 1 and -9.4 kcalxmol 1 for prazosin, SUL-150 and SUL-151 respectively. Prazosin and SUL-150 formed contacts with PHE312 and ASP106 confirmed in prazosin binding by mutagenesis, whereas SUL-151 did not show interactions with these residues. Additionally, the chirality of SUL-150 enables the orientation of its carboxamide towards ASN179, effectively forming a hydrogen bond. Additional hydrogen bond was formed between its protonated N- terminal and TYR316.
Comparison of the binding site-interactions of the several SUL compounds with the binding SUL-150, and the non-binding of SUL-151 and SUL-132 and SUL-138, allowed the prediction that the now claimed SUL-compounds indeed have the binding properties claimed.
Claims
1. (2R) enantiomeric form of a 6-chromanol derivative for use in the prophylactic or treatment of vasoconstriction related disorders or conditions wherein said 6-chromanol derivative is chosen from the group consisting of (6-hydroxy-2,5,7,8-tetramefhylchroman-2- yl)(piperazin-l-yl)methanone; (6-hydroxy-2,5,7,8-tetramefhylchroman-2- yl)(morpholino)methanone; N-(benzyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide, N- (4-fluorobenzyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide; 6-hydroxy-N-((S)-2- hydroxy-l-phenylethyl)-2,5,7,8-tetramethylchroman-2-carboxamide; N-(phenyl)-6-hydroxy- 2,5,7, 8-tetramethylchroman-2-carboxamide; 6-hydroxy-2,5,7,8-tetramethyl-N-(2- nitrophenyl)chroman-2-carboxamide; 6-hydroxy-2,5,7,8-tetramethyl-N-(3-nitrophenyl)chroman-2- carboxamide; N-(4-fluorophenyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide; methyl 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)benzoate; N-( (R)-2-amino-2-oxo-l- phenylethyl)-6-hydroxy-2,5, 7,8-tetramethylchroman-2-carboxamide; (6-hydroxy-2,5,7,8- tetramethylchroman-2-yl)((S)-2-(hydroxymethyl )pyrrolidin-l-yl )methanone; 2-(((4- fluorobenzyl)amino)methyl)-2,5,7,8-tetramethylchroman-6-ol; 2-(((S)-2-
(hydroxymethyl)pyrrolidin-l-yl)methyl)-2,5,7,8-tetramethylchroman-6-ol; 2-((((S)-2-hydroxy-l- phenylethyl)amino)methyl)-2,5,7,8-tetramethvlchroman-6-ol; 2-(((S)-2- (hydroxymethyl)pyrrolidin-l-yl)methyl)-2,5,7,8-tetramethvlchroman-6-ol; 2-(((R-2- (hydroxymethyl)pyrrolidin-l-yl)methyl)-2,5,7,8-tetramethylchroman-6-ol; ( 6-hydroxy-5, 7- diisopropyl-2,8-dimethylchroman-2-yl)(piperazin-l-yl)methanone; l-( 6-hydroxy-2,5, 7 ,8- tetramethylchroman-2-carbonyl )-pyrrolidine-S-2-carboxvlic acid, and pharmaceutically acceptable salts thereof.
2. The (2R) enantiomeric form of a 6-chromanol derivative for use according to claim 1, wherein said 6-chromanol derivative is chosen from the group consisting of the 2R enantiomer of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone; N- (benzyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide; N-(phenyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide; methyl 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxamido)benzoate; (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(morpholino)methanone, and pharmaceutically acceptable salts thereof.
3. The (2R) enantiomeric form of a 6-chromanol derivative for use according to claim 2, wherein said 6-chromanol derivative is chosen from the group consisting of the 2R enantiomer of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(morpholino)methanone, and (6- hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone.
4. The (2R) enantiomeric form of a 6-chromanol derivative for use according to claim 3, wherein said 6-chromanol derivative is (R)(6-hydroxy-2,5,7,8-tetramefhylchroman-2- yl)(piperazin-l-yl)methanone and pharmaceutically acceptable salts thereof.
5. The (2R) enantiomeric form of a 6-chromanol derivative for use according to any one of the claims 1 to 4, wherein said vasoconstriction related disorder is selected from the group consisting of pulmonary hypertension, portal hypertension, vasospastic diseases, Raynaud's disease, acrocyanosis, livedo reticularis, post-traumatic dystrophy, occlusive diseases associated with inflammation, (pre)eclampsia, and Buerger's disease.
6. The (2R) enantiomeric form of a 6-chromanol derivative for use according to any one of the claims 1 to 5, wherein said prophylaxis or treatment of vasoconstriction related disorders or conditions is mediated by inhibition of the al adrenoceptor.
7. The (2R) enantiomeric form of a 6-chromanol derivative for use according to claim 6, wherein said prophylaxis or treatment of vasoconstriction related disorders or conditions is selected from pulmonary arterial hypertension, heart failure with preserved ejection fraction and cardiac hypertrophy and fibrosis.
8. The (2R) enantiomeric form of a 6-chromanol derivative, wherein said 6- chromanol derivative is chosen from the group consisting of the 2R enantiomer of (6-hydroxy- 2,5,7, 8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone; N-(benzyl)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide; N-(phenyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxamide; methyl 4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)benzoate; (6- hydroxy-2,5,7,8-tetramethylchroman-2-yl)(morpholino)methanone, and pharmaceutically acceptable salts thereof .
9. The (2R) enantiomeric form of a 6-chromanol derivative of claim 8, wherein the derivative is (2R)(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-l-yl)methanone and pharmaceutically acceptable salts thereof.
10. The compound of claim 8 or 9 for use as a medicament.
11. The compound for use according to any one of claims 1-7 and 10, wherein the compound is used in an amount sufficient to achieve a concentration of 1 μΜ or higher.
12. The compound for use according to claim 11, wherein the compound is used in an amount sufficient to achieve a concentration of about 10 μΜ or higher.
13. Pharmaceutical dosage form comprising the compound for use according to any one of claims 1-7 and 10-12, wherein the compound is present in an amount of 10 mg - 500 mg, preferably 100 - 500 mg.
14. Pharmaceutical dosage form according to claim 13, wherein the dosage form is a solid, preferably solid oral dosage form.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18769288.4A EP3672593B1 (en) | 2017-08-25 | 2018-08-23 | Medicaments for the treatment of vasoconstriction related diseases or disorders |
US16/640,785 US12156862B2 (en) | 2017-08-25 | 2018-08-23 | Medicaments for the treatment of vasoconstriction related diseases or disorders |
ES18769288T ES3013118T3 (en) | 2017-08-25 | 2018-08-23 | Medicaments for the treatment of vasoconstriction related diseases or disorders |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NLN2019446 | 2017-08-25 | ||
NL2019446 | 2017-08-25 | ||
NLN2020985 | 2018-05-24 | ||
NL2020985 | 2018-05-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2019038361A1 true WO2019038361A1 (en) | 2019-02-28 |
Family
ID=63579308
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2018/072735 WO2019038361A1 (en) | 2017-08-25 | 2018-08-23 | Medicaments for the treatment of vasoconstriction related diseases or disorders |
Country Status (4)
Country | Link |
---|---|
US (1) | US12156862B2 (en) |
EP (1) | EP3672593B1 (en) |
ES (1) | ES3013118T3 (en) |
WO (1) | WO2019038361A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022058620A1 (en) * | 2020-09-21 | 2022-03-24 | Sulfateq B.V. | Chromanol compounds for treatment of heart failure |
WO2023163596A1 (en) * | 2022-02-28 | 2023-08-31 | Sulfateq B.V. | Chromanol compounds for treatment or prophylaxis of ageing-associated disorders |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110933933B (en) * | 2018-07-18 | 2022-12-27 | 温州医科大学 | Method for treating myopia and application of prepared medicine |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014098586A1 (en) | 2012-12-19 | 2014-06-26 | Sulfateq B.V. | Compounds for protection of cells |
WO2015193365A1 (en) | 2014-06-17 | 2015-12-23 | Sulfateq B.V. | 6-hydroxy-2,5,7,8-tetramethylchroman-compounds for the treatment of chronic obstructive airway diseases |
WO2016188766A1 (en) | 2015-05-22 | 2016-12-01 | Sulfateq B.V. | Compound for the prophylaxis or treatment of organ damage |
-
2018
- 2018-08-23 WO PCT/EP2018/072735 patent/WO2019038361A1/en unknown
- 2018-08-23 EP EP18769288.4A patent/EP3672593B1/en active Active
- 2018-08-23 ES ES18769288T patent/ES3013118T3/en active Active
- 2018-08-23 US US16/640,785 patent/US12156862B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014098586A1 (en) | 2012-12-19 | 2014-06-26 | Sulfateq B.V. | Compounds for protection of cells |
EP2935232A1 (en) * | 2012-12-19 | 2015-10-28 | Sulfateq B.V. | Compounds for protection of cells |
WO2015193365A1 (en) | 2014-06-17 | 2015-12-23 | Sulfateq B.V. | 6-hydroxy-2,5,7,8-tetramethylchroman-compounds for the treatment of chronic obstructive airway diseases |
WO2016188766A1 (en) | 2015-05-22 | 2016-12-01 | Sulfateq B.V. | Compound for the prophylaxis or treatment of organ damage |
Non-Patent Citations (7)
Title |
---|
"Remington: The Science and Practice of Pharmacy", 2003, LIPPINCOTT WILLIAMS & WILKINS, PHILADELPHIA |
"Remington's Pharmaceutical Sciences", 1991, MACK PUB. CO. |
"Treatise on Controlled Drug Delivery", 1992, MARCEL DEKKER, INC. |
BING HAN ET AL: "The anti-inflammatory and bronchodilating properties of the novel pharmacological compound Sul-121", INTERNET CITATION, 24 April 2015 (2015-04-24), pages 10, XP002742182, Retrieved from the Internet <URL:http://www.nvfarmaco.nl/assets/docs/Abstracts_NVF_Voorjaarsdag_2015.pdf> [retrieved on 20150714] * |
BING HAN ET AL: "The novel compound Sul-121 inhibits airway inflammation and hyperresponsiveness in experimental models of chronic obstructive pulmonary disease", SCIENTIFIC REPORTS, vol. 6, no. 1, 27 May 2016 (2016-05-27), XP055526648, DOI: 10.1038/srep26928 * |
LEE, DIFFUSION-CONTROLLED MATRIX SYSTEMS, pages 155 - 198 |
RON; LANGER, ERODIBLE SYSTEMS, pages 199 - 224 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022058620A1 (en) * | 2020-09-21 | 2022-03-24 | Sulfateq B.V. | Chromanol compounds for treatment of heart failure |
NL2026511B1 (en) * | 2020-09-21 | 2022-05-24 | Sulfateq Bv | Compounds for treatment of heart failure |
CN116322661A (en) * | 2020-09-21 | 2023-06-23 | 萨尔法泰克有限公司 | Chromanol compounds for the treatment of heart failure |
WO2023163596A1 (en) * | 2022-02-28 | 2023-08-31 | Sulfateq B.V. | Chromanol compounds for treatment or prophylaxis of ageing-associated disorders |
NL2031091B1 (en) * | 2022-02-28 | 2023-09-07 | Sulfateq Bv | Chromanol compounds for treatment or prophylaxis of ageing and ageing-associated disorders |
Also Published As
Publication number | Publication date |
---|---|
EP3672593A1 (en) | 2020-07-01 |
EP3672593B1 (en) | 2024-12-18 |
US20210128523A1 (en) | 2021-05-06 |
ES3013118T3 (en) | 2025-04-11 |
US12156862B2 (en) | 2024-12-03 |
EP3672593C0 (en) | 2024-12-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5212176A (en) | R(+)-terazosin | |
AU2010241513B9 (en) | Use of brimonidine for preventing and reducing the severity of stress-associated conditions | |
US12156862B2 (en) | Medicaments for the treatment of vasoconstriction related diseases or disorders | |
HUE032948T2 (en) | Opioid receptor ligands and methods for their use and production | |
JP2003530429A (en) | Methods and compositions for modulating alpha adrenergic receptor activity | |
SK287828B6 (en) | 5-Halo-tryptamine derivatives used as ligands of 5-HT6 and/or 5-HT7 serotonin receptors | |
JPWO2020050253A1 (en) | Drugs for diabetic peripheral neuropathy | |
IE51736B1 (en) | Imidazoline derivative | |
KR101747486B1 (en) | Therapeutic agent for pain | |
CN103989682B (en) | Therapy with centhaquin | |
US11730741B2 (en) | 6-chromanol derivatives for use as a medicament | |
WO2006035617A1 (en) | α2 RECEPTOR BLOCKING AGENT CONTAINING INDOLE DERIVATIVE AS ACTIVE INGREDIENT AND VASODILATOR | |
US20070259945A1 (en) | Method for treating pain | |
EP4218818A1 (en) | Alpha-2 adrenergic receptor antagonist | |
US20020040018A1 (en) | Subtype selective melatonergics | |
KR20110071079A (en) | Pharmaceutical Composition for Novel Treatment of Invasive Soluble Pain | |
KR20210040228A (en) | Anti-histamine compounds, pharmaceutical compositions and medical-use thereof | |
WO2025096783A1 (en) | Enhancers of particulate guanylyl cyclase receptor b | |
JPWO2003068263A1 (en) | Antihypertensive drug | |
JPH11506094A (en) | 3 (2H) -pyridazinone derivatives and pharmaceutical compositions containing the compounds | |
WO2002076399A2 (en) | YOHIMBINE DIMERS EXHIBITING BINDING SELECTIVITES FOR α2 ADRENERGIC RECEPTORS | |
KR20190103385A (en) | 4,4-diphenylpiperidine compound or a pharmaceutically acceptable salt thereof, pharmaceutical composition and use thereof | |
WO2004071433A2 (en) | Methods of treating disease |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18769288 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2018769288 Country of ref document: EP Effective date: 20200325 |